Is EFHC1 p.Pro5Thr (c.13C>A) pathogenic?

EFHC1 p.Pro5Thr (c.13C>A) is classified Uncertain significance in EFHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-16). AlphaMissense: likely benign (0.0623); Very rare (popmax 0.00329%, sas).

How common is EFHC1 p.Pro5Thr (c.13C>A) in the general population?

EFHC1 p.Pro5Thr (c.13C>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about EFHC1 p.Pro5Thr (c.13C>A)?

AlphaMissense predicts likely benign (score 0.0623) — an in-silico prediction, not a clinical call.

EFHC1 p.Pro5Thr

c.13C>A · VCV3274679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0623	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.61, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	17.37	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,096 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000496% 8/1,614,122 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,365
European (non-Finnish)	0.000424%	236,008

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EFHC1
Protein: p.Pro5Thr
Coding: c.13C>A
MANE Select: NM_018100
Type: single nucleotide variant
Location: chr6:52420423 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 2 PDB
Residue 5: the 'required for its localization in the mitotic spindle and interaction with alpha-tubulin' region

Full EFHC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFHC1 p.Pro5= Conflicting classifications of pathogenicity ★ same residue
EFHC1 p.Pro5Arg Uncertain significance ★ ⚠ same residue
EFHC1 p.Ala445Thr Uncertain significance ★★ ⚠ same type
EFHC1 p.Ala529Glu Uncertain significance ★★ ⚠ same type
EFHC1 p.Ala590Pro Uncertain significance ★★ ⚠ same type
EFHC1 p.Ala83Val Uncertain significance ★★ ⚠ same type
EFHC1 p.Ala88Val Uncertain significance ★★ ⚠ same type
EFHC1 p.Arg118Cys Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/efhc1-p-pro5thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown